Search for α1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an α(1D)-adrenoceptor antagonist

Two novel quinazolines (2 and 3) related to both prazosin and its open analogue 1 were synthesized, and their biological profile at α1- adrenoceptor subtypes was assessed by functional assays in rat isolated tissues, namely prostatic vas deferens (α(1A)), spleen (α(1B)) and aorta (α(1D)). Furthermore, the binding profile of 3 was assessed at native α2 and D2 receptors, and cloned human 5-HT(1A) receptors, in comparison to prazosin, (+)-cyclazosin, 1 and BMY 7383. It turned out that the cystamine- bearing quinazoline 3 (cystazosin) has a reversed affinity profile relative to (+)-cyclazosin owing to a higher affinity for α(1D)-adrenoceptors and a significantly lower affinity for the α(1A) and α(1B) subtypes. Furthermore, in comparison to BMY 7378, cystazosin (3) displays a much better specificity profile since it has lower affinity for D2 and 5-HT(1A) receptors.